Identification of inositol polyphosphate 4-phosphatase type II as a novel tumor resistance biomarker in human laryngeal cancer HEp-2 cells

Abstract

Although tumor resistance remains a significant impediment to successful radiotherapy, associated regulatory markers and detailed molecular mechanisms underlying this phenomenon are not well defined. In this study, we identified inositol polyphosphate 4-phosphatase type II (INPP 4B) as a novel marker of radioresistance by systematically analyzing Unigene libraries of laryngeal cancer. INPP 4B was highly expressed in radioresistant laryngeal cancer cells and was induced by treatment with either radiation or anticancer drugs in various types of cancer cells. Ectopic INPP 4B overexpression increased radioresistance and anticancer drug resistance by suppressing apoptosis in HE p-2 cells. Conversely, INPP 4B depletion with small interfering RNA resensitized HE p-2 as well as A549 and H1299 cells to radiation-and anticancer drug-induced apoptosis. Furthermore, radiation-induced INPP 4B expression was blocked by inhibition of extracellular signalregulated kinase (ERK). INPP 4B depletion significantly attenuated radiation-induced increases in Akt phosphorylation, indicating an association of INPP 4B-mediated radioresistance with Akt survival signaling. Taken together, our data suggest that ERK-dependent induction of INPP 4B triggers the development of a tumor-resistance phenotype via Akt signaling and identify INPP 4B as a potentially important target molecule for resolving the radioresistance of cancer cells.